Integration of cancer stemness and neoantigen load to predict responsiveness to anti-PD1/PDL1 therapy.

Background: Anti-programmed cell death 1/programmed cell death ligand 1 (PD1/PDL1) therapy is an important part of comprehensive cancer therapy. However, many patients suffer from non-response to therapy. Tumor neoantigen burden (TNB) and cancer stemness play essential roles in the responsiveness to therapy. Therefore, the identification of drug candidates for anti-PD1/PDL1 therapy remains an unmet need. Methods: Three anti-PD1/PDL1 therapy cohorts were obtained from GEO database and published literatures. Cancer immune characteristics were analyzed using CIBERSORTX, GSVA, and ESTIMATE. WGCNA was employed to identify the gene modules correlated with cancer TNB and stemness. A machine-learning method was used to construct the immunotherapy resistance score (TSIRS). Pharmacogenomic analysis was conducted to explore the potential alternative drugs for anti-PD1/PDL1 therapy resistant patients. CCK-8 assay, EdU assay and wound healing assay were used to validate the effect of the predicted drug on cancer cells. Results: The therapy response and non-response cancer groups have different microenvironment features. TSIRS was developed based on tumor neoantigen and stemness. TSIRS can effectively predict the outcomes of patients with anti-PD1/PDL1 therapy in training, validation and meta cohorts. Meanwhile, TSIRS can reflect the characteristics of tumor microenvironment during anti-PD1/PDL1 therapy. PF-4708671 is identified as a potential alternative drug for patients with resistance to anti-PD1/PDL1 therapy. It possesses significant inhibitive effect on the proliferation and migration of BGC-823 cells. Conclusion: TSIRS is an effective tool in the identification of candidate patients who will be benefit from anti-PD1/PDL1 therapy. Small molecule drug PF-4708671 has the potential to be used in anti-PD1/PDL1 therapy resistant patients.

Effectiveness of brief mindfulness intervention for college students' problematic smartphone use: The mediating role of self-control.

BACKGROUND: Mainland China has the most smartphone users worldwide, especially among college students, while mindfulness intervention can significantly alleviate the level of problematic smartphone use. We examined the effects of a brief mindfulness intervention on problematic smartphone use and investigated if this effect is mediated by self-control. METHODS: Participants were recruited randomly from a university in Beijing of China. Forty-four college students were assigned to a mindfulness group or a control group. The mindfulness group took part in a brief (30 min) single-session mindfulness intervention. The control group was instructed to listen to a neutral news audio recording for the same duration (30 min). The Freiburg Mindfulness Inventory, Mobile Phone Addiction Tendency Scale, and Self-control Scale were used to measure state mindfulness, problematic smartphone use, and self-control of college students at pre-intervention and post-intervention, respectively. RESULTS: Two-way repeated-measures ANOVA revealed that the mindfulness group had significant improvements in state mindfulness (p = .049) and self-control (p = .012), and had significant alleviation in problematic smartphone use (p < .001) at post-intervention. In the regression model, self-control had a mediating effect between mindfulness intervention and problematic smartphone use (95% CI [0.490, 7.216]). CONCLUSIONS: A brief single-session mindfulness intervention can alleviate the level of problematic smartphone use and increase the level of state mindfulness and self-control compared to the control group. Self-control can completely mediate the efficacy of the mindfulness intervention in reducing problematic smartphone use.

Examining the Effects of Brief Mindfulness Training on Athletes' Flow: The Mediating Role of Resilience.

BACKGROUND: Flow is characterized by the strong concentration in competitions, eliminating irrelevant thoughts and emotions, integrating all tasks, and continuing the competition smoothly even in challenging situations. The present study was into whether or not brief mindfulness training can improve athletes' flow and further explore the mediating effect of resilience in the intervention. METHODS: The 2 (experimental conditions) × 2 (time) mixed design was used in this study. Fifty-seven student-athletes were recruited and randomly assigned into either a brief mindfulness group (n = 29) or a control group (n = 28). Before and after the intervention, every participant completed a self-report measure including mindfulness, flow, and resilience. RESULTS: Participants in the brief mindfulness group showed increased mindfulness, flow, and resilience (p < 0.001) after brief mindfulness training; when putting resilience change (B = 0.30, 95% CI [0.031, 0.564]) into the equation, the direct (95% CI [3.156, 13.583]) and indirect (95% CI [0.470, 5.048]) effects of mindfulness training were both significant. CONCLUSION: It was concluded that brief mindfulness training could significantly improve athletes' flow and resilience, and resilience partly mediated the effects of brief mindfulness training on flow.

HepG2 cells biospecific extraction and HPLC-ESI-MS analysis for screening potential antiatherosclerotic active components in Bupeuri radix.

HepG2 cells biospecific extraction method and high performance liquid chromatography-electrospray ionization-mass spectrometry (HPLC-ESI-MS) analysis was proposed for screening of potential antiatherosclerotic active components in Bupeuri radix, a well-known Traditional Chinese Medicine (TCM). The hypothesis suggested that when cells are incubated together with the extracts of TCM, the potential bioactive components in the TCM should selectively combine with the receptor or channel of HepG2 cells, then the eluate which contained biospecific component binding to HepG2 cells was identified using HPLC-ESI-MS analysis. The potential bioactive components of Bupeuri radix were investigated using the proposed approach. Five compounds in the saikosaponins of Bupeuri radix were detected as these components selectively combined with HepG2 cells, among these compounds, two potentially bioactive compounds namely saikosaponin b1 and saikosaponin b2 (SSb2) were identified by comparing with the chromatography of the standard sample and analysis of the structural clearance characterization of MS. Then SSb2 was used to assess the uptake of DiI-high density lipoprotein (HDL) in HepG2 cells for antiatherosclerotic activity. The results have showed that SSb2, with indicated concentrations (5, 15, 25, and 40 µM) could remarkably uptake dioctadecylindocarbocyanine labeled- (DiI) -HDL in HepG2 cells (Vs control group, *P<0.01). In conclusion, the application of HepG2 biospecific extraction coupled with HPLC-ESI-MS analysis is a rapid, convenient, and reliable method for screening potential bioactive components in TCM and SSb2 may be a valuable novel drug agent for the treatment of atherosclerosis.

The significant inhibition on CYP3A caused by radix Aconiti single herb is not observed in the Wutou decoction: The necessity of combination therapy of radix Aconiti.

ETHNOPHARMACOLOGICAL RELEVANCE: Wutou (WT, Radix Aconiti), the mother root of Aconitum carmichaelii Debx., is a famous Chinese herb against rheumatoid arthritis. In Chinese clinics, PWT is often prepared as a decoction in combination with other herbs, such as Wutou decoction (WTD). The present study aimed to compare the effects of PWT single herb and WTD on CYP3A activity ex vivo and in vivo. MATERIALS AND METHODS: In the ex vivo study, CYP3A activity was determined by using testosterone (Tes) as a specific probe. Levels of Tes and its metabolite 6ß-hydroxytestosterone (6ß-OH-Tes) were measured using a validated ultra-performance liquid chromatography (UPLC) method. CYP3A protein and mRNA levels were measured by using Western blot and real-time PCR, respectively. In the in vivo study, CYP3A activity was determined by using buspirone (BP) as a specific probe. The plasma concentrations of BP and its primary metabolites, namely, 1-(2-pyrimidinyl) piperazine (1-PP) and 6'-hydroxybuspirone (6'-OH-BP), were determined using a validated UPLC-tandem mass spectrometry (UPLC/MS/MS) method. RESULTS: Compared with the control group, the formation rates of 6ß-OH-Tes from Tes ex vivo significantly decreased in groups treated with PWT at the tested doses, and this decrease was accompanied by a striking decrease in CYP3A protein and mRNA levels. However, a significant increase was observed in the ratios in the WTD groups compared with PWT single herb groups. In vivo, both formation ratios of 6'-OH-BP and 1-PP from BP showed no significant change in the WTD group. CONCLUSIONS: PWT can significantly inhibit CYP3A activity ex vivo at the tested doses because of the down-regulation of CYP3A protein and mRNA expression levels. WTD can significantly reverse the inhibition caused by PWT. WTD also had no significant effect on CYP3A activity in vivo. Results implied that the use of PWT as a part of the WTD prescription rather than PWT single herb is more appropriate in clinics.

Pinelliae rhizoma, a toxic chinese herb, can significantly inhibit CYP3A activity in rats.

Raw Pinelliae Rhizoma (RPR) is a representative toxic herb that is widely used for eliminating phlegm or treating cough and vomiting. Given its irritant toxicity, its processed products, including Pinelliae Rhizoma Praeparatum (PRP) and Pinelliae Rhizoma Praeparatum cum Zingibere et Alumine (PRPZA), are more commonly applied and administered concomitantly with other chemical drugs, such as cough medications. This study aimed to investigate the effects of RPR, PRP, and PRPZA on CYP3A activity. Testosterone (Tes) and buspirone (BP) were used as specific probe substrates ex vivo and in vivo, respectively. CYP3A activity was determined by the metabolite formation ratios from the substrates. Ex vivo results show that the metabolite formation ratios from Tes significantly decreased, indicating that RPR, PRP, and PRPZA could inhibit CYP3A activity in rats. CYP3A protein and mRNA levels were determined to explore the underlying mechanism. These levels showed marked and consistent down-regulation with CYP3A activity. A significant decrease in metabolite formation ratios from BP was also found in PRPZA group in vivo, implying that PRPZA could inhibit CYP3A activity. Conclusively, co-administration of PR with other CYP3A-metabolizing drugs may cause drug-drug interactions. Clinical use of PR-related formulae should be monitored carefully to avoid adverse interactions.